Category Archives: Pediatric Gastroenterology Liver Disease

Markers for Outcomes in Neonates with Acute Liver Failure

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PS Rolfes et al. J Pediatr 2024; 272: 114080. Establishing Neonate-Specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel Neonatal Acute Liver Failure Scores Predict Patient Outcomes

Methods: A single-center, retrospective chart review (n=51) was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (international normalized ratio ≥ 2 or prothrombin time ≥ 20s and liver dysfunction).  This excluded infants who responded to a single dose Vit K injection or fresh frozen plasma. The age at presentation was 4.7 in survival with native liver (SNL) group and 6.9 in the non-SNL group.

Key findings:

  • The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (16%). All three patients with HLH died. Ischemia had the highest survival rate of 64% compared to 40% for infectious ALF, and 50% for GALD-ALF.
  • Overall survival with native liver (SNL) rate was 43% (n = 22).
  • Alpha-fetoprotein levels were higher in SNL group on admission (mean 46,471) compared to transplant/non-survival group (mean 2450). Peak values were 165,000 compared to 17,650. AFP levels remained significant after removing GALD patients with SNL group now with 17,500 mean on admission compared to 1006 in non-SNL group.
  • Ammonia levels were lower in SNL group on admission 48 vs 70 and at peak: 83 vs 172.
  • A neonatal ALF (nALF) model was developed: 1.29 x Admission INR +0.985 x Admission Ammonia (micromol/L). This score was significantly lower (mean 48.1) in SNL group compared to non-SNL group of 76.2.
  • A peak nALF model: 0.982 x Peak PT +0.985 x Peak Ammonia (micromol/L) performed even better than admission nALF model. SNL group had mean value of 118 compared to 223 for non-SNL group (P <0.001)

In the discussion, the authors note that AFP may have high prognostic value at time of admission (similar to neonatal ALF model), especially in Non-GALD patients. AFP Is a “biomarker for hepatic regeneration….Similar to our findings, several adult studies have shown that elevated AFP levels are associated with favorable outcomes in non-oncologic liver diseases…Specifically, it has been shown that in ALF, rising levels of AFP during hospitalization are associated with favorable outcomes.”

My take: Both the AFP and the neonatal ALF score had similar prognostic value for SNL.

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Flowers on Channel Islands (off coast of California)

Autoimmune Diseases in Patients with Primary Sclerosing Cholangitis Plus One

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A Lundberg Bave et al. Hepatology 2024; 80: 527-535. Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives

Methods: Using National Swedish registries, the authors evaluated a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives.

Key findings:

  • After excluding inflammatory bowel disease and autoimmune hepatitis, the prevalence of autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77
  • Highest odds were seen for celiac disease [OR: 4.3], sarcoidosis [OR: 2.74], diabetes type 1 [OR: 2.91], and autoimmune skin disease [OR: 2.15]
  • First-degree relatives of individuals with PSC had higher odds of developing IBD [OR: 3.25], autoimmune hepatitis [OR: 5.94], and any autoimmune disease than relatives of the comparators [OR: 1.34] 

My take: Keep an eye out for other autoimmune diseases in patients (& their 1st-degree relatives) with PSC.

Related blog posts:

Briefly noted: BB Lai et al. Hepatology 2024; 80: 511-526. Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency–related cholestasis Key finding: “Patients with the TJP2-C genotype carrying PPTMs [predicted protein-truncating mutation] in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.”

Blog Case Report: A Persistent Elevated AST in Teen with IBD and ADHD

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A recent case reminded me of the quote by Helena Ravenclaw in Harry Potter: “”If you have to ask, you’ll never know. If you know, you need only ask.”

One of my colleagues recently diagnosed a teenage boy with ulcerative colitis. His past medical history was notable for ADHD. At the time of his evaluation, he was noted to have an elevated AST.

Labs:

  • June: AST 143, ALT 8, Hepatitis B immune
  • August: AST 190, ALT 10, Albumin 4.7, T protein 7.3, T bili 0.4, D bili 0.1, Alk phos 168; GGT 10, CPK 93

The concern at the time was whether his elevated AST should preclude using his ADHD medicine and whether there was an underlying liver disease. Based on the pattern of liver enzyme abnormalities, it was suspected that the patient had macro AST. A blood test was sent to the Mayo clinic and confirmed this diagnosis:

“”The sample was investigated for the presence of macro AST by polyethylene glycol (PEG) precipitation. Serum AST activity = 316 U/L. The AST result post-PEG precipitation = 22 U/L. The results obtained are positive for the presence of macro AST (93% of activity precipitated with PEG). Based on validation studies performed at the Mayo Clinic, a cut-off of >80% AST activity precipitated by PEG indicates the presence of macro AST.” This test is rarely ordered at the Mayo Clinic and is ordered as a miscellaneous test; it is not on the Mayo Clinic’s regular test menu.

Internet description of macro AST: Macro-aspartate aminotransferase (macro AST) is a rare, benign condition that causes a persistent elevation of aspartate aminotransferase (AST) levels in the blood. It’s caused by the binding of AST to immunoglobulins, which results in a high molecular weight macroenzyme that’s excreted from the serum more slowly than normal.

My take: Macro AST diagnosis is useful –it helps eliminate the concern for other conditions. Since it is quite uncommon, it is easier to think of this problem once you have seen it before.

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Fibrosis and Steatotic Liver Disease -Who Needs to be Followed by Hepatology?

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N Ma et al. JPGN 2024; 79:229–237. Fibrosis and steatotic liver disease in US adolescents according to the new nomenclature

Methods: Among 1410 adolescents (12–19 years) in NHANES (2017-March, 2020), the controlled attenuation parameter (CAP) of transient elastography (TE) was used to define steatosis and fibrosis (TE ≥ 7.4 kPa). Obesity and alanine aminotransferase (ALT) ≥ 80 U/L were used to identify adolescents qualifying for hepatology referral according to practice guidelines.

Key findings:

  • At the supplier (EchoSens)-recommended CAP threshold of 240 dB/m, 30.5% of adolescents had steatotic liver disease (SLD) and about 85% of adolescents with NAFLD met criteria for MASLD. At a CAP threshold of 270 dB/m, SLD prevalence was about 16% in adolescents. The other 15% of NAFLD patients do not meet diagnostic criteria MASLD and would receive a diagnosis of cryptogenic SLD or possible MASLD
  • At higher CAP thresholds, MASLD/NAFLD concordance increased and approached 100%.
  • Among adolescents with MASLD-fibrosis, only 8.8% had overweight/obese and ALT ≥ 80 U/L. Thus, more than 90% of adolescents in this group would not merit hepatology evaluation based on current guidelines.

My take: This study identifies potential problems with current thresholds for which patients need to be seen by pediatric hepatologists. This will be even more important as effective pharmaceuticals become available.

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Channel Islands off the California coast

Selecting Patients with Biliary Atresia for Variceal Endoscopy Screening

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Y-C Ling et al. JPGN 2024;79:222–228. Performance of Baveno VII criteria for the screening of varices needing treatment in patients with biliary atresia

Methods: This retrospective study enrolled 48 BA patients (23 females and 25 males) who underwent an esophagogastroduodenoscopy (EGD) and transient elastography at a mean age of 11.18 ± 1.48 years. Transient elastography (Fibroscan® 502 Touch; Echosens) was applied for the LSM assessment in all BA patients recruited in this study.

Clinically-significant portal hypertension (CSPH) of Baveno VI criteria recommend avoiding upper endoscopies for cirrhotic patients with liver stiffness <20 kPa and platelets>150 × 10-9 cells/L (favorable Baveno VI status), and the CSPH of the expanded Baveno VI criteria as the exclusion of subjects with LSM < 25 kPa and platelet count >110 × 10-9 cells/L. (Ref: D Thabut et al. Gastroenterol 2019. Validation of Baveno VI Criteria for Screening and Surveillance of Esophageal Varices in Patients With Compensated Cirrhosis and a Sustained Response to Antiviral Therapy)

CSPH of Baveno VII criteria was defined as LSM ≥ 25 kPa and excluded patients with LSM < 15 kPa and platelet count ≥150 × 10-9 /L. Subjects with LSM between 20 and 25 kPa and platelets <150 × 10-9 /L or LSM between 15 and 20 kPa and platelets <110 × 10-9/L are also defined as CSPH. (Ref: Baveno VII criteria Ref: M Mendizabal et al. Annals of Hepatology; 2024: 29: 101180. Evolving portal hypertension through Baveno VII recommendations)

Key findings:

  • The sensitivity and negative predictive value of Baveno VI and Baveno VII criteria for the prediction of varices needing treatment (VNT) in BA patients were both 100% and100%, respectively

In the discussion, the authors note that the utility of the Baveno VII criteria for adults. “The real‐world data showed the CSPH defined by Baveno VII criteria predicts a five‐times increase in the risk of liver decompensation in chronic active liver disease patients.”

My take: This study shows that the combination of LSM and platelet counts using the Baveno VI or VII criteria help select patients with BA who need upper endoscopy to screen for varices needing treatment. These criteria also identify patients needing liver transplantation.

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Channel Islands off California coast
View from Griffith Park, Los Angeles

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Updated Diagnostic Accuracy of Serum Matrix Metalloproteinase-7 (MMP-7) for Biliary Atresia

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S Pandurangi et al. Hepatology 2024; 80: 152-162 Open Access!.Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort

Methods: MMP-7 was measured in serum samples of 399 infants (North America)18 with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays.

Key findings:

  • On the single-plex assay, MMP-7 generated an AUROC of 0.90. At cutoff 52.8 ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA.
  • MMP-7 outperformed other parameters. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77–0.86), stool color = 0.68 (CI: 0.63–0.73), and pathology = 0.84 (CI: 0.76–0.91).  Obstructive features on pathology were the second-best predictor of BA.
  • GGT cutoff was 267.5 U/L (per personal communication with senior author) with sensitivity of 86.6%, and specificity of 77.4%
  • Similar results were found with TR-FRET assay with cut-off of 18.2 ng/mL.
  • 6% (False-negatives) of BA patients had MMP-7 levels below the cutoff
  • 22% (False-positives) of non-BA patients had MMP-7 levels above the cutoff. This included 7 of 8 choledochal cyst patients, 8 of 17 with A1AT, and 13 of 98 with indeterminate cholestasis

In the discussion, the authors note that MMP-7 has performed better in studies with Asian populations, MMP-7 could be useful for dried blood spots in newborns, and could be useful as a measure of successful HPE; continued elevation of MMP-7 has been associated with hepatic fibrosis.

My take: This study shows that MMP-7 is not a perfect assay but often quite helpful. The exact cutoff depends on the specific assay that is utilized. Also, this study shows that checking for A1AT and checking an ultrasound to exclude choledochal cyst need to continue to be done early in the evaluation process.

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Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

Liver Briefs: MASLD with T1DM, ESPGHAN Pediatric HCV Recommendations, Age of Kasai in Europe

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  1. F Koutny et al. JPGN 2024; https://doi.org/10.1002/jpn3.12194. Open Access! Poorly controlled pediatric type 1 diabetes mellitus is a risk factor for metabolic dysfunction associated steatotic liver disease (MASLD): An observational study

Study population, n=32,325. Key finding:  Inadequately controlled T1D (HgbA1c >11%) was associated with a higher hazard ratio ((HR: 1.54) of elevated ALT values compared to children with controlled T1D over an observation period extending up to 5.5 years. When both elevated HbA1c (>11%) and overweight were present, the HR was 2.71.

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2. G Indolfi et al. JPGN 2024; 78:957–972. ESPGHAN recommendations on treatment of chronic hepatitis C virus infection in adolescents and children including those living in resource-limited settings

Summary of Recommendations:

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3. F Lacaille et al. JPGN 2024; 78:1374–1382. Awareness, referral and age at Kasai surgery for biliary atresia in Europe: A survey of the Quality-of-Care Task Force of ESPGHAN

Key finding: Data from 785 infants diagnosed with BA from 2015 to 2019 from 18 centers in 15 countries revealed a mean age at referral to tertiary center of 55 days (similar to results obtained in Europe 10–30 years earlier)

Related blog posts:

Biliary Atresia

HCV:

Relooking at 6-Year Data of Maralixibat for Alagille Syndrome

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BE Hansen et al. Hepatology 2024; 79: 1279-1292. Open Access! Event-free survival of maralixibat-treated patients with Alagille syndrome compared to a real-world cohort from GALA

This study compared “6-year outcomes from maralixibat trials with an aligned and harmonized natural history cohort from the Global ALagille Alliance (GALA) study.”

Based on a quick review, some the data appears to overlap a recent report in the same journal: RJ Sokol et al. Hepatology 2023; 78: 1698-1710. Open Access! Predictors of 6-year event-free survival in Alagille syndrome patients treated with maralixibat, an ileal bile acid transporter inhibitor (See blog post: Six Year Data for IBAT Inhibitor Treatment for Alagille Syndrome).

In the current study, “event-free survival, defined as the time to first event of manifestations of portal hypertension (variceal bleeding, ascites requiring therapy), surgical biliary diversion, liver transplant, or death, was analyzed by Cox proportional hazards methods.”

Key findings:

  • Event-free survival in the maralixibat cohort (n=84) was significantly better than the GALA cohort (n=469) (HR, 0.305)
  • Transplant-free survival showed similar results (aHR, 0.33)

In their discussion, the authors note that much of the improvement in event-free survival is due to improvement in pruritus which is a main indication for liver transplantation. They speculate that improvement in event-free survival is also related to more broad-based clinical improvement (observed in ICONIC study), perhaps due to reduction in retained hepatic bile acids.

One of the limitations, reliance on a historical control, is discussed. “Historical control comparison is useful when there are ethical concerns regarding the recruitment of patients for long-term control arms requiring several years of study in life-threatening or debilitating diseases.”

My take: In this real-world comparison, Maralixibat, clearly was associated with improved outcomes. How much of this was due to relief of intractable pruritus and how much of this may be due to other biologic factors remains uncertain.

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How Well Does BARD Criteria Work for Diagnosing Cholangitis Following a Kasai Repair for Biliary Atresia

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M Madadi-Sanjani et al. JPGN Reports 2024: https://doi.org/10.1002/jpr3.12071. Open Access! Retrospective analysis of the standardized BARD criteria for acute cholangitis in biliary atresia patients

This retrospective study examined the Biliary atresia and Related Diseases (BARD) criteria for diagnosis of acute cholangitis in BA patients within the first year following Kasai hepatoportoenterostomy (HPE).

Key findings:

  • Of 185 consecutive BA patients, 59 (32%) had at least one episode of cholangitis within the first year after HPE
  • The correlation between the clinician’s impression and the standardized BARD definition was very strong (r = 0.8)
  • Only 41% of patients believed by their physicians to have cholangitis had fever
  • 70% had increased WBC and/or CRP, and/or procalcitonin
  • 90% had increased bilirubin/GGT, 68% had increased transaminases
  • Only one (1/59) patient in their cohort had a positive blood culture and only one (1/59) patient had bile lakes identified
  • 56/59 children (94.9%), at least one laboratory or radiological item (group B) was pathologic at cholangitis diagnosis

My take: There really is not a precise way to diagnose cholangitis following HPE. Given how infrequently they are identified, it looks like both blood culture and bile lakes are not useful in establishing the diagnosis given. Overall, these criteria correlate well with how clinicians establish the diagnosis of cholangitis in at-risk children.

The Standardized Biliary Atresia and Related Diseases (BARD) cholangitis guidelines for the diagnosis of suspected and confirmed cholangitis within the first year following hepatoportoenterostomy for biliary atresia. *Vomiting, poor feeding, irritability. PCT, procalcitonin.

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Genetic Testing for Pediatric Acute Liver Failure of Indeterminate Origin

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D Lenz et al. Hepatology 2024; 79: 1075-1087. Open Access! Genetic landscape of pediatric acute liver failure of indeterminate origin

Background: ” In US and European cohorts, the underlying etiology [of PALF] remained unclear in about half of cases, hampering clinical management including disease-specific therapies, particularly decision-making regarding liver transplantation.” The associated editorial (pg 970-972) by Squires and Horslen note that standardized evaluation of PALF can lower the indeterminate cases to ~30%.

This study had 96 authors! (I think). In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. 

Key findings:

  • Whole-exome sequencing (WES) established a genetic diagnosis in 37% of cases (97/260)
  • Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%)
  • Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. The underlying pathophysiologies in those with abnormal WES were mitochondrial diseases (45%) and disorders of vesicular trafficking (28%)

Discussion points:

  • 55% of patients in this series had no evidence of an underlying genetic disorder. “According to Squires et al,32 the fraction of PALF cases with unknown etiology is particularly high in the first 3 years of life, which is the age range in which our study demonstrates the highest molecular diagnostic yield by WES.”
  • Rapid turnaround of genetic testing is essential in order to have an important clinical impact. A “short period of time as the clinical situation typically is critical and decisions are time-sensitive.” Yet the editorial noted that “rapid” testing in most laboratories require 1-6 months.

My take: Genetic testing is important for indeterminate PALF and may help in determining whether to proceed with a liver transplant.

Related blog post: Bookmark This Article on Pediatric Acute Liver Failure

Dale Chihuly Glass Art
This is a cup that Jay Hochman made!